Vaccines have long been used for the prevention of infectious diseases, such as viral or microbial infections. The cell-mediated arm of the immune system is extensively involved in providing the host with the ability to defend, recover from infections and to prevent further infections by the same antigen. Cell-mediated immune mechanisms are also thought to be useful against cancer.
Dendritic cells (DCs), the most potent antigen-presenting cells (APC), play a central role in the initiation and regulation of immune responses. They have the unique ability to prime naive T cells and to elicit and induce effective cytotoxic T lymphocyte (CTL) responses. DC precursors are present in the circulating blood and can quickly be recruited to sites of infection or inflammation. When DC precursors differentiate into immature DCs they become very effective in taking up and processing exogenous protein antigens. In response to various maturation stimuli, such as bacterial and viral components expressing Toll-like receptor (TLR) ligands, inflammatory cytokines and/or specific T cell interactions (CD40/CD40-ligand interactions), they initiate a differentiation process leading to decreased antigen uptake and processing capacities and enhanced expression of co-stimulatory and MHC molecules. Importantly, signal strength and persistence of the signals induced by direct pathogen recognition (eg, TLRs) or CD40 ligation has been shown to be critical determinants of specific DC functions. DCs are therefore terminally induced by activation-factors at peripheral sites, to fulfill 1 of 2 mutually exclusive functions—that is, either to migrate to lymph nodes (as mature migratory DCs) for efficient T-cell interaction, or to condition the microenvironment by producing large quantities of inflammatory mediators including chemokines and cytokines (as mature proinflammatory DCs).
Existing cancer immunotherapy strategies that focus on DCs are all based on the premise that the quality of the T cell response depends mainly on the ability of migratory DCs to process and present tumor antigens to T cells in secondary lymphoid organs and thus create a tumor-specific CTL response, which leads to an immunological attack on the cancer cells. Data from different mouse tumor models have shown that such response can been trigged according to one out of three main strategies, well known to a person skilled in the art. These immunotherapeutic anticancer strategies are now actively tested in humans but all with limited success.
The first strategy is to activate and mature antigen-loaded migratory DCs from the tumor-bearing patient ex vivo and subsequently reintroduce them to the same patient. Antigen-loading is typically performed by adding tumor associated antigens (lysed tumor cells, protein, peptides or nucleic acids coding for such antigens) to monocyte-derived immature DCs followed by activation/maturation of antigen-loaded DCs with different combinations of inflammatory factors. The reintroduced DCs are supposed to migrate to draining lymph nodes where they prime tumor-specific T lymphocytes. DC-primed T lymphocytes, particularly CTLs, then travel to the tumor site where they subsequently induce tumor-cell apoptosis.
In the clinical setting, ex vivo manipulation of patients own, i.e. autologous, DCs is however time consuming and exposes the patient to increased risk of infection. Also, the manipulation process in which the DCs are pulsed with tumor antigens and activated to migratory DCs that efficiently present tumor antigens is tedious.
The second main strategy, which circumvents the need for ex vivo propagation of patient-derived migratory DCs, comprises administration of tumor antigens, including irradiated allogeneic tumor cells, or plasmids coding for tumor antigens, into intact normal tissues, including subcutaneous or intramuscular injections. The tumor antigens are supplemented with so called adjuvants, which are aimed to trigger a DC-mediated immune response in vivo. Most commonly, chemokines, cytokines or plasmids coding for these factors, and/or DC-maturating factors such as tumor necrosis factor α (TNF-α), and/or TLR agonists are used as adjuvants.
However, administration of exogenous tumor antigen is a tedious process.
The third main strategy, which also circumvents the need for ex vivo propagation of patient-derived migratory DCs, included in the first main strategy, and additionally circumvents the need of exogenous tumor antigen, included in the second main strategy, regards an adjuvant which is injected directly into tumors. Thus, the adjuvant is aimed at targeting DCs in vivo and the tumor of the patient acts as a source for tumor associated antigens. Adjuvants that have been tested are similar to those described in the second main strategy: chemokines, cytokines or plasmids coding for these factors, and/or DC-maturating factors such as TNF-α, and TLR agonists. However, a viable tumor may be a poor source of tumor associated antigen for recruited immature DCs, due to insufficient numbers of dying, preferably induced by apoptosis, tumor cells that can be engulfed by these DCs.
All the abovementioned three strategies have been tested in human cancer patients, but with limited success. Hence, there is an obvious need for more efficient therapeutic vaccines and improved methods of treatment of cancer.